Studies suggest that a relatively high proportion of women with sporadic breast cancer exhibit an abnormally high level of radiosensitivity as measured by the frequency of chromosomal aberrations induced by ionizing radiation exposure (such as X- and gamma-ray) in the G2 phase of PHA stimulated lymphocytes. Because ionizing radiation causes DNA strand breaks and unrepaired DNA double-strand breaks can lead to chromosomal breaks, increased G2 chromosomal radiosensitivity is a marker of cellular repair capacity for chromosomal damage induced by endogenous or exogenous mutagens. DNA double-strand break repair (DSBR), including non-homologous end joining (NHEJ) and homologous recombination (HR), is responsible for repair of DNA double-strand breaks that may lead to chromosomal breaks. About a dozen DNA repair genes involved in these pathways are polymorphic, but their role in G2 chromosomal radiosensitivity has not been fully investigated, particularly in the etiology of breast cancer. The major goal of this R03 application is to utilize an existing pilot study of breast cancer funded by our institutional seeds funds that had helped collect and store blood samples from breast cancer patients and cancer-free-controls. Using this existing resource, we propose to investigate the role of G2 chromosomal radiosensitivity in the etiology of breast cancer and to identify genetic variants that may correlate with the radiosensitivity phenotype. Our specific aims are: 1): To determine the associations between the G2 chromosomal radiosensitivity (phenotype) and risk of breast cancer in young Caucasian (<=55 years) women. This aim will be achieved by evaluating chromosomal aberrations in short-term cultured lymphocytes that have already been treated by gamma-irradiation, harvested and stored in -20 degrees C freezer from among 200 cases and 200 controls and additional recruitment. We hypothesize that a high-radiosensitivity phenotype as measured by the gamma-ray-induced mutagen sensitivity is associated with increased risk of breast cancer. 2): To determine the correlation between polymorphisms of three select DNA repair genes (XRCC3, XRCC7 and RAD51) involved in DSBR and the G2 chromosomal radiosensitivity (phenotype) and their modulation of risk breast cancer associated with increased radiosensitivity in these women. We hypothesize that adverse genotypes of these select genes correlate with G2 chromosomal radiosensitivity and modulate risk of breast cancer associated with (72 chromosomal radiosensitivity. The ultimate goal of this study is to identify individuals at high risk and help design new clinical and public health strategies aimed at preventing and controlling breast cancer. Towards this goal, this study will help identify variants of the susceptibility genes that will correlate with radiosensitivity phenotype and subgroups of individuals of young (<=55 years) women at increased risk of developing breast cancer.